DNA constituting the essentiality of gene is regulated by various factors and thereby its genetic information is controlled. That is, the transcription from DNA to mRNA is controlled and regulated by a plurality of DNA binding proteins which recognize the sequence of several to dozens of bases on the gene and combine thereto. AP-1 known as one of such DNA binding proteins was identified as an important transcription factor dealing with proliferation of cells (Biochem. Biophys. Acta, Vol. 1072, Pages 129-157, 1991). Further, in some succeeding studies, it became apparent that AP-1 extensively participates in the induction of the expression of many genes and in the control and regulation of biological phenomena.
When AP-1 binds to AP-1 binding sequence (5′-TGAGTCA-3′) on genes, it exhibits a function as a transcription factor. As substances having such a sequence on the gene, proteins such as collagenases, stromelysin, metallothionein, interleukin-2 and the like and viruses such as SV40, polyoma virus and the like are known (Cell, Vol. 49, Pages 729-739, 1987).
Hitherto, as therapeutic drugs for may diseases, therapeutic drugs for controlling the function of proteins participating in the pathology such as enzymes and receptors have been developed. It is considered that, however, in the diseases caused by a quantitative abnormality of functional molecules existing in cells or on cell membranes, a treatment in the true sense is to control the quantity of transcription of the genes of the functional molecule and normalize the quantity of its expression rather than to control the activity of the functional molecules.
The gene expression and production of these functional proteins are controlled by a plurality of transcription factors. Since a transcription binding AP-1 sequence is common to exist in the promoter region of many genes, it is expected that various diseases may be effectively treated by controlling the AP-1 activity.
Up to today, it has been disclosed that glucocorticoids (Cell, Vol. 82. Pages 1189-1204, 1990) and retinoid derivatives (Nature, Vol. 372, Pages 107-111, 1994) can suppress the activity of AP-1. The action mechanism is considered as follows at the present time. Thus, these substances can form a complex together with respective receptor, and association of the complex with AP-1 can suppress of the binding of AP-1 to gene.
Steroidal agents used as therapeutic drugs for various diseases are known to exhibit a controlling action at the stage of expression of gene through intermediation of a glucocorticoid receptor. In fact, it has been reported that steroidal agents inhibit the activity of AP-1 and suppresses the production of cytokines and other proteins (Cell, Vol. 62, Pages 1189-1204, 1990). On the other hand, the use of steroidal agents are restricted from the viewpoint of hormone actions and side effects, and their side effects have a problem when they are administered excessively and/or for a long period of time.
In the recent years, a novel chemical drug is usually developed by a rational drug design base on the three-dimensional structure of biopolymers such as proteins (e.g., receptors and enzymes) and nucleic acid, which play an important physiological role (Shin Seikagaku Jikken Koza, Vol. 13, Pages 291-337, Tokyo Kagaku Dojin, 1993).
For applying this method, it is indispensably necessary to know the three-dimensional structure of the target bipolymer. The three-dimensional structure of the complex of transcription factor AP-1 and the complexes of its binding sequence have been elucidated by X ray crystallographic analysis (Nature, Vol. 373, Pages 257-261, 1995).
Accordingly, it has been desired to develop an agent for prevention and/or treatment of diseases in which overexpression of AP-1 participates, which suppresses the excessive expression of a wide variety of genes on the basis of AP-1 inhibitory action with lessened side reactions.